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Cited by 116Adenosine and Purinergic SignalingCalcium signaling and nucleotide metabolismBiochemical and Molecular Research

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P2X7 on Mouse T Cells: One Channel, Many Functions

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Rissiek, Björn, Haag, Friedrich, Boyer, Olivier, Koch-Nolte, Friedrich, Adriouch, Sahil·2015·Frontiers in Immunology
DOI 10.3389/fimmu.2015.00204PMC PMC4436801
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Abstract

The P2X7 receptor is an adenosine triphosphate (ATP)-gated cation channel that is expressed by several cells of the immune system. P2X7 is best known for its proinflammatory role in promoting inflammasome formation and release of mature interleukin (IL)-1β by innate immune cells. Mounting evidence indicates that P2X7 is also an important regulatory receptor of murine and human T cell functions. Murine T cells express a sensitive splice variant of P2X7 that can be activated either by non-covalent binding of ATP or, in the presence of nicotinamide adenine dinucleotide, by its covalent ADP-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Prolonged activation of P2X7 by either one of these pathways triggers the induction of T cell death. Conversely, lower concentrations of ATP can activate P2X7 to enhance T cell proliferation and production of IL-2. In this review, we will highlight the molecular and cellular consequences of P2X7 activation on mouse T cells and its versatile role in T cell homeostasis and activation. Further, we will discuss important differences in the function of P2X7 on human and murine T cells.

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Crossref · 10.3389/fimmu.2015.00204

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Figure 1 Cellular consequences of P2X7 activation on mouse T cells. (A) Non-covalent binding of ATP or covalent ARTC2.2-mediated ADP-ribosylation results in P2X7 channel gating and in the influx of calcium and sodium ions and the efflux of potassium. (B) P2X7 activation triggers the activation of ADAM10 and ADAM17 that catalyze the shedding of the ectodomains of various cell surface proteins such as CD27, CD62L and IL-6R. (C) P2X7 activation leads to phosphatidylserine (PS) externalization, formation of a non-selective membrane pore allowing the uptake of fluorescent molecules such as DNA staining dyes, and ultimately to cell death.
Figure 1 Cellular consequences of P2X7 activation on mouse T cells. (A) Non-covalent binding of ATP or covalent ARTC2.2-mediated ADP-ribosylation results in P2X7 channel gating and in the influx of calcium and sodium ions and the efflux of potassium. (B) P2X7 activation triggers the activation of ADAM10 and ADAM17 that catalyze the shedding of the ectodomains of various cell surface proteins such as CD27, CD62L and IL-6R. (C) P2X7 activation leads to phosphatidylserine (PS) externalization, formation of a non-selective membrane pore allowing the uptake of fluorescent molecules such as DNA staining dyes, and ultimately to cell death.CC BY · PubMed Central
Figure 2 P2X7-dependent alteration of T cells can be prevented by blocking the activity of ARTC2.2. Freshly prepared spleen CD4+Foxp3+ Tregs and liver CD3+CD1d-tetramer+ NKT cells remain unaffected when kept at 4°C but rapidly shed CD27 when re-incubated at 37°C due to NAD+ release during cell preparation and ARTC2.2-mediated ADP-ribosylation of P2X7 (left panel). These cells also rapidly shed CD62L and expose phosphatidylserine at their cell surface (not illustrated here). Intravenous injection of an anti-ARTC2.2 blocking nanobody (s + 16a) before harvesting of the organs prevents ADP-ribosylation of P2X7 during cell manipulation and P2X7-dependent CD27 shedding when cells are re-incubated at 37°C (right panel).
Figure 2 P2X7-dependent alteration of T cells can be prevented by blocking the activity of ARTC2.2. Freshly prepared spleen CD4+Foxp3+ Tregs and liver CD3+CD1d-tetramer+ NKT cells remain unaffected when kept at 4°C but rapidly shed CD27 when re-incubated at 37°C due to NAD+ release during cell preparation and ARTC2.2-mediated ADP-ribosylation of P2X7 (left panel). These cells also rapidly shed CD62L and expose phosphatidylserine at their cell surface (not illustrated here). Intravenous injection of an anti-ARTC2.2 blocking nanobody (s + 16a) before harvesting of the organs prevents ADP-ribosylation of P2X7 during cell manipulation and P2X7-dependent CD27 shedding when cells are re-incubated at 37°C (right panel).CC BY · PubMed Central
Figure 3 Modulation of human T cells phenotype, response to mitogenic stimulation, and survival by ATP and P2X7. P2X7-stimulation on the surface of human T cell may have different consequences which could hypothetically depend on the extracellular concentration of ATP, P2X7 density, expression of CD39 and other ATPases, on the nature of T cell subsets, and on their activation status. (A) High concentration of extracellular ATP have been reported to culminate, at least in vitro, in the induction of cell death possibly through the induction of massive membrane depolarization and permeabilization. (B) At lower ATP concentration and/or if cells express a low level of surface P2X7 and/or a high level of ATP-catabolizing enzymes, P2X7-activation could participate instead in T cell costimulation by enhancing the intracellular level of Ca2+, an universal second messenger (76, 78). This may result in the stimulation of NFAT, MAPKs, and IL-2 secretion (69, 70, 72), and in the activation of metalloproteases that catalyze the shedding of CD62L and of other cell surface proteins (79). (C) In some studies, TCR stimulation by mitogenic activators was shown to promote ATP release through pannexin 1 favoring autocrine/paracrine T cell co-stimulation (69, 70, 72). (D) TCR stimulation was also found to stimulate the translocation of pannexin 1 at the immunological synapse together with P2X1 and P2X4 (80). P2X7 is also found within the immunological synapse even if it is not actively translocated within the immunological synapse and remains instead uniformly distributed across the cell surface. This mechanism may thus serve to provide a tonic co-stimulatory signal during physiological activation of a T cell in contact with antigen-presenting cells by promoting the local release of ATP within the immunological synapse, and the local activation of P2X receptors expressed by T cell as well as by antigen-presenting cells.
Figure 3 Modulation of human T cells phenotype, response to mitogenic stimulation, and survival by ATP and P2X7. P2X7-stimulation on the surface of human T cell may have different consequences which could hypothetically depend on the extracellular concentration of ATP, P2X7 density, expression of CD39 and other ATPases, on the nature of T cell subsets, and on their activation status. (A) High concentration of extracellular ATP have been reported to culminate, at least in vitro, in the induction of cell death possibly through the induction of massive membrane depolarization and permeabilization. (B) At lower ATP concentration and/or if cells express a low level of surface P2X7 and/or a high level of ATP-catabolizing enzymes, P2X7-activation could participate instead in T cell costimulation by enhancing the intracellular level of Ca2+, an universal second messenger (76, 78). This may result in the stimulation of NFAT, MAPKs, and IL-2 secretion (69, 70, 72), and in the activation of metalloproteases that catalyze the shedding of CD62L and of other cell surface proteins (79). (C) In some studies, TCR stimulation by mitogenic activators was shown to promote ATP release through pannexin 1 favoring autocrine/paracrine T cell co-stimulation (69, 70, 72). (D) TCR stimulation was also found to stimulate the translocation of pannexin 1 at the immunological synapse together with P2X1 and P2X4 (80). P2X7 is also found within the immunological synapse even if it is not actively translocated within the immunological synapse and remains instead uniformly distributed across the cell surface. This mechanism may thus serve to provide a tonic co-stimulatory signal during physiological activation of a T cell in contact with antigen-presenting cells by promoting the local release of ATP within the immunological synapse, and the local activation of P2X receptors expressed by T cell as well as by antigen-presenting cells.CC BY · PubMed Central

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  1. Freedman, 1999, ATP-evoked Ca2+ transients and currents in murine thymocytes: possible role for P2X receptors in death by neglect, Eur J Immunol, 29, 1635, 10.1002/(SICI)1521-4141(199905)29:051635::AID-IMMU16353.3.CO;2-2 · DOI

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Metadata

Authors
Rissiek, B., Haag, F., Boyer, O., Koch-Nolte, F., & Adriouch, S.
Affiliations
  • Universität Hamburg (DE)
  • Inserm (FR)
Corresponding author
Adriouch, Sahil
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2015-05-19
Volume
6
Pages
204-204
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2015.00204
PMC
PMC4436801
OpenAlex
W1564355150
Cited by
116
References
81
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 15 · 2020: 13 · 2019: 14 · 2018: 15 · 2017: 11 · 2016: 12
FWCI
1.62
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (SFB 877, HA2369/5)
  • Institut National de la Santé et de la Recherche Médicale
  • Normandie Université
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
P2X7 receptor, T cells, ATP-gated cation channels, ADP-ribosylation, T cell death, T cell proliferation, interleukin-2, T cell homeostasis, T cell activation, splice variants

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